Method for the preparation of oxygenated benzo{8 c{9 phenanthridine compounds

ABSTRACT

A practical method is provided for the preparation of oxygenated benzo(c)phenanthridine compounds related to nitidine.

United States Patent [1 1 Zee-Cheng et al.

[4 1 Oct. 14, 1975 METHOD FOR THE PREPARATION OF OXYGENATED BENZO[C]PHENANTHRIDINE COMPOUNDS [75] Inventors: Kwang Yuen Zoe-Cheng;

Chia-Chung Cheng, both of Kansas City, Mo.

[73] Assignee: The United States of America as represented by the Secretary of the Department of Health, Education, and Welfare,.Washington, DC.

22 Filed: Feb. 28, 1974 21 Appl. No.: 446,896

[52] US. Cl... 260/286 Q; 260/289 A; 260/289 AZ; 260/515 R; 260/561 R; 260/592; 260/600; 260/340.5; 424/258 [SI] Int. Cl. C07D 215/58 [58] Field of Search 260/286 0, 287 R, 289 AZ [56] References Cited Primary Examiner-Donald G. Daus Assistant ExaminerDavid E. Wheeler [57] ABSTRACT A practical method is provided for the preparation of oxygenated benzo[c]phenanthridine compounds related to nitidine.

8 Claims, No Drawings 1 METHOD FOR THE PREPARATION OF OXYGENATED BENZO[C ]PHENANTHRID1NE COMPOUNDS This invention relates to a practical method for the synthesis of nitidine and related oxygenated benzo [c]phenanthridine compounds. This invention further relates to the preparation of new compounds related to nitidine.

Nitidine chloride (1, R and R are methyl, R and R ll) taken together are methylene, R is methyl, R is H,

and X is C1) as well as 5, 6-dihydro-6-methoxynitidine 1 (ll, R and R are methyl, R and R taken together are methylene, R is methyl, and R is methoxy) are 0Q R 0 8 I: 0R

U R10 Xe lyne and the nitidine compounds conform to a proposed N--O-O triangular pharmacophore hypothesis for antileukemic activity, as set forth by Zee'Cheng et I al., J. Pharm. Sci., Volume 59 (1970), at 1630, it is apparent that a practical synthetic route to oxygenated benzo[c]phenanthridine compounds is needed.

The N-OO pharmacophore hypothesis is based on the observation that several nonalkylating antileukemic agents have a common structural feature consisting of a triangulation composed of one nitrogen and two oxygen atoms with rather definite interatomic distances. it is proposedthat this structural.characteristic may contribute to the in vivo binding to one of the pertinent receptor sites involvedin leukemia geneses.

Prior art on the synthesis ofbenzo[c]phenanthridine compounds include a Pschorr-type synthesis by ring closure of a diazotized aromatic amine to 21 fused ring structure reported by Dyke et al., Tetrahedron, Volume 24 (1968), at 1467, and the work of Arthur et al., J.

, t I CR4" 29 CH0 1 OH 5CH3C, 3

Chem. Soc. (1961), at 4010. Neither of these reported routes is practical for the reason that the yields are unreasonably low.

Other available art on the synthesis of phenanthridine derivatives include Hellerba'ch, US. Pat. No. 3,243,438; Hellerbach et al., US. Pat. No 3,499,901; and van der Burg, U.S.-.Pat.No. 3,661,916. However, none of these references provides a feasible route to oxygenated benzo[c]phenanthridine compounds as exemplified by formulas L and Thus, there is a continuing need for a practical synthetic route giving reasonable yields of oxygenated benzo[c]phenanthridine compounds represented by formulas l and 11.

It has been found, in accordance with this invention, that oxygenated benzo[c]phenanthridine compounds represented by formula I can be prepared'in a practical fashion and further that hitherto unknown phenanthridine derivatives evaluated by standard procedures are active against L-12l0 and P388 mouse leukemia in mice and can be prepared by the method of this invention. Among the new compounds prepared in accordance with this invention are allonitidine compounds represented by the formula:

and 5,6-dihydro-6-alkoxynitidine compounds of the formula:

phenone derivative, represented by formula 1}],

VIII

R o l 1 7 R CH R CH aromatizing the tetrahydrobenzo[clphenanthridine OR (CH 80 Xylene XII under alkaline conditions to form a chalcone. represented byformula Y condensing the chalcone with a cyanide under acidic conditions to form a ketobutyronitrile, represented by formula \[Jz hydrolyzing the ketobutyronitrile in a one-step basecatalyzed reaction to a ketobutyric acid, represented by formula VJ}; I

reducing the ketobutyric acid to a butyric acid, represented by formula Vlllr cyclizing the butyric acid to a tetralone, represented by formula IX, using phosphorus pentachloride and stannic chloride as cyclizing agents;

converting the tetralone to a formamide, represented by formula as, in a modified Leuckart reaction wherein the reaction mixture is heated at about l80l85 C.;

cyclizing the formamide to a tetrahydrobenzo[c]- phenanthridine, represented by formula )5}, with phosphorus oxychloride;

Toluene HOAc over palladium on charcoal catalyst in an inert fluid of the phenyl polysiloxane type to a benzo[c]phenanthridine, represented by formula X LI;

and quaternizing the benzo[c]phenanthridine to L As to the foregoing synthetic sequence, it will be understood that the definitions of R R R R R R and X used in reference to the quaternized benzo[c]- phenanthridine, apply also to the substituents on compounds represented by formulas Ill-)Ql, as well as to the compounds represented by formula llfor the dihydro derivatives.

It will further be understood that the term oxygenated benzaldehyde derivative" includes compounds represented by formula Ill, oxygenated acetophenone derivative includes compounds represented by formula IX; chalconeiincludes compounds represented by formula X and the like.

phenanthridines because of four variations from previous Syntheses, namely,

l. the one-step base-catalyzed hydrolysis of the ketobutyronitrile (XI) to the ketobutyric acid (VII) provides a better yield than hitherto available by 8&7; ventional two-step hydrolytic procedure via a ketoamide; 2. butyric acid (VIII) is eyclizedto tetralone (IX) in higher yield than obtained by the conventional cyclization procedure using phosphorusoxychloride by lowtemperature cyclization with phosphorus pentachloride and stannic chloride; 3. use of a higher than customary reaction temperature, that is, about l80-185 C., in the Leuckart reaction between the tetralone (IX) and formamide increased the yieldof the formamid e derivative and 4. the aromatization of tetrahydrobenzo[c]phenanthridine (lg) to the phenanthridine (Jill) using an inert fluid of the phenylpolysiloxane type, is much more selective than prior procedures, in which large amounts of undesired 11,l2-dihydrobenzo[c]- phenanthridine compounds are obtained.

In the case of nitidine methosulfate (I, R, and R are methyl, R and R taken together are methylene, R is methyl, R is H-, and X is methosulfate), the overall yield from acetopiperone was For the synthesis of allonitidine methosulfate (I, R, and R taken together are methylene, R and RTare methyl, R is methyl, R is H-, and X is methosulfate), the overall yield from dimethoxyacetophenone was 9%.

In the synthesis of compounds represented by formula I it will be understood that the term C, C alkyl, H, benzyl as applied to R,, R R R, and R includes any of the normal or branched chain hydrocarbon radicals having from one to six' carbon atoms, including methyl, ethyl, propyl, isopropyl, the butyl isomers, the amyl isomers, and the hexyl isomers. However, the preferred alkyl groups are the C, C straight chain alkyl groups, that is, methyl, ethyl,, propyl and butyl. Of these, methyl is particularly preferred.

It will further be understood that R in formulairepresents I-I- or an alkoxy group based on any C, C alkyl group, as previously defined. The preferred substituents represented by R are I-I and the C, C, normal alkoxy groups, that is, methoxy, ethoxy, propoxy and butoxy. The most preferred are H and methoxy.

The anion represented by X in formulaLmay be any monovalent negatively charged species which bonds ionically with nitrogen to form a quaternary salt. Typical of anions within the definition of- X are chloride, bromide, iodide, hydroxide, methosulfate, and the monovalent equivalent of polyvalent anions such as sulfate, phosphate and the like. Of the foregoing anions, chloride, methosulfate and hydroxide are preferred in the practice of this invention. Methosulfate and chloride are particularly preferred.

As used in the specification and claims, a cyanide means sodium or potassium cyanide. The cyanide is condensed with the chalcone LY) under acidic conditions to give a ketobutyronitrile "One-step base-catalyzed reaction, as used in the specification and claims, means the reaction between the ketobutyronitrile derivative (VI) and an alkali, such as sodium hydroxide, potassium hydroxide or lithium hydroxide, in a medium of aqueous ethanol, to yield the ketoacid (VII).

Cyclization of butyric acid (VIII) to tetralone (IX), involving the use of a combination of phosphorus pentachloride and stannic chloride, is customarily done in an inert solvent, such as chloroform.

Conditions for the preparation of the formamide X from the tetralone (I X) include a temperature in the range from about 180 to about 185 C., although this is the temperature generally recommended for conversion of cyclic ketones to the corresponding primary amines, following a hydrolysis step omitted here. See Moore, in Organic Reactions", Volume V (1949), after 301. In the synthesis of nitidine itself, a high temperature heating step is preferably followed by heating at a less elevated temperature, such as initially heating at about l-185 C. and then heating at about l 45 C. The success of the aromatization of tetrahydrobenzo[c]-phenanthridines (X I) to benzophenanthridines (XII) depends on the use ofa particular inert fluid. that is, a phenyl polysiloxane as exemplified by Dow Corning Fluids Nos. 550 and 710. The catalyst used in this procedure is a conventional palladium on charcoal catalyst. The reaction temperature is generally above 250 C., usually in the range from about 255 to about 260 C.

Normally, benzo[c]phenanthridines (XI I) are quaternized with dimethyl sulfate to produce a methosulfate I which is converted by reaction with an ionic chloride, e.g., sodium chloride or potassium chloride, is a combination of solvents, e.g., xylene and nitromethane, to the chloride (I, X is Cl The hydroxide (I, X is OH) is obtained from the halide in the usual man ner, e.g., reaction in aqueous solution with silver hydroxide.

The benzo[c]phenanthridine methosulfate I R is methyl, X is methosulfate) is also the intermediate from which 5,6-dihydrobenzo[c]phenanthridine II is obtained by reaction with aqueous ammonia. When the reaction between a benzo[c]phenanthridinium methosulfate and aqueous ammonia is followed by a reaction with methanol or any other alcohol, 5,6-dihydro-6- alkoxybenzo[c]phenanthridines are obtained (II, R, is methyl, R is alkoxy).

The novel allonitidine compounds of this invention, as indicated by the formula above, are characterized by a methylenedioxy substituent at the 8 and 9 positions of the phenanthridine system and by alkyl groups R, and R in the alkoxy groups at the 2 and 3 positions. The substituent at the 6-position, denoted by R is selected from the group consisting of H- and C, C straight and branched chain alkoxy. R R and R represent C C alkyl, H, benzyl, whether or straight or branched chain structure. X is any of the anions listed above.

Preferably, R R and R are methyl; R is selected from the group consisting of I-I and methoxy; and X is selected from the group consisting of chloride, hydroxide and methosulfate in the allonitidine compounds of this invention.

In the. novel 5,6-dihydro-6-alkoxynitidine compounds of this invention, R,, R R R.,,,R and R are selected independently from C, C straight and branched chain alkyl groups and R, and R taken together are methylene. The preferred novel dihydro compounds of this invention are those in which R,, R R R R and R are methyl and in which R, and R taken together are methylene and R R R and R groups are methyl.

Reference is made to two articles by Zee-Cheng et al., J. Heterucyclic Chem., Volume 1973) at 85 and 867, wherein the synthesis of nitidinc and related compounds and their biological activity is discussed. and which are hereby incorporated in this specification by reference.

Reference is also made to the standard testing procedures used in evaluating chemical agents, Protocals for Screening Chemical Agents and Natural Products Against Animal Tumors and Other Biological Systems" (3rd Ed.), Cancer Chemotherapy Reports, Part 3, Volume 3, No. 2 (1972) at 7, for Lymphoid Leukemia L- 1210, and at 9, for Lymphocytic Leukemia P-388.

The following examples illustrate the synthetic method of this invention and the preparation of novel compounds thereby.

EXAMPLE I 3,4-Dimethoxy-3,4'-methylenedioxychalcone (y R and R are methyl; R and R taken together are methylene).

3,4-Dimethoxybenzaldehyde (111; R and R are methyl) was condensed with acetopiperone (3,4-

EXAMPLE 2 .a-( 3 ,4-Dimethoxyphenyl )-y-( 3 ,4-methylenedioxyphenyD-y-oxobutyric acid (V ll; R and R are methyl; R and R taken together are methylene).

A mixture of 76 grams (0.22 mole) of a-(3,4-

dimethoxyphenyl )-y-( 3 ,4-methyledioxyphenyl )-'yoxobutyronitrile (Y l) prepared according to Arthur et al. supra, and 85 grams (2.13 moles) of sodium hydroxide in 940 milliliters of water and 330 milliliters of ethanol was refluxed on a steam bath for 10 hours. It was then cooled and acidified with stirring, with 10% hydrochloric acid to pH 1. The resulting solid was collected by filtration, washed with water, and dried to give 77 grams (95% yield) of V1}, melting point l6817l C. Recrystallization from ethanol, melting point l781 79 C.; )t max (ethanol) 230 (log 6 4.41 274 (3.97) and 307 nm (3.92).

EXAMPLE 3 2-( 3,4-Dimethoxyphenyl )-1 ,2,3,4-tetrahydro-6,7- methylene-dioxy-l-oxanaphthalene (I ZQR and R are methyl; R and R taken together are methylene).

A mixture of grams (0.056 mole) of the product of Example 2 and 2.8 grams of 10% Pd/C in 200 milliliters of acetic acid in the presence of 1 milliliter of 70% perchloric acid was hydrogenated at 55-60 C. under 4 kg./cm for 2 hours. The resulting mixture was worked up as usual to yield 20 grams (95% yield) of the acid ylll as a light brown gummy residue; )tmax (ethanol) 234,283 nm.

To a stirred suspension of 12.0 grams (0.057 mole) of phosphorus pentachloride in 50 milliliters of dry chloroform was added a solution of 19.2 grams (0.056 mole) of y l llin 160 milliliters of chloroform with icebath cooling. The mixture was stirred in the ice bath for 2 hours followed by stirring at room temperature for 16 hours. To this was added dropwise. with ice cooling. a

solution of 6.7 milliliters (0.056 mole) of anhydrous stannic chloride in 20 milliliters of chloroform in 30 minutes. The resulting mixture was stirred at ice bath temperature for 3 hours. then was poured into a mixture of 300 milliliters of 10?! hydrochloric acid and 200 grams of ice. The gummy complex in the aqueous mixture was gradually dispersed and decomposed by stirring. The mixture was extracted with chloroform (4 400 milliliters). The resulting chloroform extracts were washed successively with water, 3'71 sodium hydroxide, and water. The washings were back extracted with chloroform. The combined chloroform extracts were dried (sodium sulfate) and solvent removed in vacuo. The residue was triturated with 20 milliliters of methanol and the solid was collected by filtration to give 15.5 grams (84% yield) of 12$. melting point l67170 C. Recrystallization from methanol yielded white needles, melting point 170-172 C; )tmax (ethanol), 232 (log 64.41), 275 (4.05) and 318 nm (3.97), m/e: 326 (M EXAMPLE 4 2-( 3,4-Dimethoxyphenyl l-formamido-l ,2,3 ,4- tetrahydro-6,7-methylenedioxynaphthalene. (X5 R and R are methoxy; R and R taken together are methylene).

To a stirred mixture of 24 grams (0.074 mole) of the product of Example 3, 60 milliliters of redistilled formamide and 3.5 milliliters of formic acid was added 3.5 grams of ammonium sulfate. The reaction mixture was heated in an oil bath at l-182 C. for 6 hours with stirring. Cautious addition of one 3.5 milliliter portion of formic acid to the mixture was made each hour and there was a total of five such additions. The resulting mixture was kept at 140l45 C. for 12 hours. To the cooled mixture was added milliliters of water and 250 milliliters of chloroform. After being stirred for 15 minutes, the aqueous layer was separated and extracted with chloroform (3 X 400 milliliters); the extract was combined with the organic layer, washed with water, dried (sodium sulfate), and solvent evaporated. The resulting product was purified by column chromatography using neutral alumina and eluted with chloroform.

Evaporation of the chloroform eluate yielded a residue, which, when triturated with 20 milliliters of methanol, gave 15.9 grams (55% yield) of X melting point 168l80 C. Recrystallization from methanol raised the melting point to l85l 87 C; Amax (ethanol): 230 (log-e 4.20), 285 nm (3.90), Ash (ethanol) 293 nm (log e 3.79), m/e: 355 (M EXAMPLE 5 8,9-Dimethoxy-2,3-methylenedioxy-4b,10b,l 1,12- tetrahydrobenzo[c]phenanthridine (X l; R and R are methyl; R and R taken together are methylene).

To a stirred suspension of 7.5 grams (0.021 mole) of the product of Example 4 in 75 milliliters of dry toluene at C. was added 19 milliliters of redistilled phosphorus oxychloride. A yellow crystalline solid separated from the clear solution. The mixture was heated at that temperature for a total of 20 minutes and cooled to 40 C. The solid was collected by filtration, washed with toluene and ether,.and dried to give 7.8 grams of the crude hydrochloride salt, melting point 21 1214 C. dec. This was suspended in 70 milliliters of warm methanol, basified with methanolic ammonia, and

monohydrate, melting with decomposition cooled. The resulting white crystals were collected by filtration, washed with methanol, and dried to give 4.7 grams (66% yield) of melting point 188-190 C. Recrystallization from methanol and pyridine yielded white crystals, melting point l98200 C. with decomposition; Amax (ethanol) 233 (log 6 4.52), 285 nm (4.07), m/e: 337 (M EXAMPLE 6 8,9-Dimethoxy-2,3-methylenedioxybenzo[clphenanthridine (2,3-dimethoxy-12-methyl[1,3-]bezodioxolo[5,6-c]phenanthridine, (X11; R and R are methyl; R and R taken together are methylene).

A mixture of 1 gram of the product of Example 5 and 0.3 gram of 30% palladium-on-charcoal catalyst prepared according to Mozingo, Organic Synthesis, Coll. Vol. 111 (1955), at 685, in milliliters of Dow Corning 550 Fluid was heated under nitrogen at 255-260 C. in an oil bath for 2 hours with stirring. The mixture was cooled and diluted with 50 milliliters of chloroform. The solid was removed by filtration and extracted continuously with chloroform. The combined filtrate and extracts were evaporated under reduced pressure to yield a pasty substance. This was triturated with 15 milliliters of ethanol. The resulting solid product was collected by filtration, washed with ethanol, and dried to give 0.85 gram (85% yield) of X11, melting point 276-278 C. An analytical sample was obtained as white crystals by recrystallization from pyridine and ethanol, melting point 278-280 C., )tmax (ethanol) 229 (log 6 4.36), 274 (4.73), 311 (4.15), 348 (3.60), and 367 nm (3.46); Ash (ethanol) 278 (4.71), 330 nm (3.89): thin layer chromatography Rf: 0.48 (chloroform, silica gel) Rf: 0.75 (chloroform, alumina); m/e: 333 (M*), 335 (M* 2H, trace). The product was found identical with that prepared by the previously reported dry-heating method, Arthur et al., supra.

Aromatization of the product of Example 5 to 2511 was also done by heating a mixture of X1 and sulfur. The yield was comparable.

EXAMPLE 7 Attempted aromatization of Attempted aromatization of the product of Example 5 with palladium-on-charcoal in quinoline or with diphenyl disulfide yielded a solid, melting point 23l-233 C., which was identified as the 11,12- dihydronitidine derivative. )tmax- (chloroform) 242 (log 6 4.28), 270 (4.52), 277 (4.60) and 326 nm (4.34). Anal. Calcd. for C H NO (335.4): C, 71.63; H, 5.11; N, 4.18. Found: C, 71.30; H, 5.09; N, 4.31; m/e: 335 (M*, 100%).

EXAMPLE 8 Nitidine Methylsulfate R and R are methyl; R and R taken together are methylene; R is methyl; R is H; X is CH SO To a solution of 2.2 grams (0.0066 mole) of the product of Example 6 in 25 milliliters of xylene and 50 milliliters of nitrobenzene at 160 C. was added 5 milliliters of dimethyl sulfate. This was heated at 180-190 C. for 5 minutes whereupon a yellow solid separated from the reaction mixture. The mixture was cooled and diluted with 300 milliliters of ether. The solid was collected by filtrationand washed with ether (3 X 100 milliliters) to give 2.3 grams (73% yield) of nitidine methosulfate at 307-308 C. Recrystallization from methanol yielded an analytically pure sample. melting point 310-312 C. (literature: Arthur et al., supra. melts with decomposition at 306-307 C.) The product was dried at 135 C. in vacuo before analysis; Mnax (ethanol) 230 (log 6 4.38), 272 (4.68), 300 (4.54), 328 (4.50). and 388 nm (4.00), A sh (ethanol) 280 nm (4.62). No moving spots were noted under either of the following thin-layer chromatography examinations: chloroform. silica gel or chloroform, alumina. Anal. Calcd. for C H NO S" H O (477.5): C, 55.34; H, 4.86; N, 2.93. Found: C. 55.63; H, 4.58; N, 2.98; m/e: 333 (M dimethylsulfate-water).

EXAMPLE 9 Nitidine Chloride (1; R and R are methyl; R and R taken together are methylene; R is methyl; R is H-; X is Cl In 100 milliliters of warm C.) water was rapidly dissolved 250 milligrams 10.53 millimole) of the product of Example 8.

It was filtered immediately [the water-insoluble substance (48 milligrams), which separated from the aqueous solution, was identified as the unmethylated compound Xllby comparison of their infrared spectra and thin-layer chromatograms] into 200 milliliters of stirred 15% sodium chloride solution. The light yellow solid, which separated from the saline solution by filtration, was dried and dissolved in 150 milliliters of boiling methanol. On cooling, a light, flocculent white solid separated from the solution. It was collected by filtration and dried to yield 30 milligrams of solid, melting point 303-305 C. The solid was identified as the hydrochloride salt of X l l by comparison of its infrared spectrum with that of an authentic sample.

Anal. Calcd. for C H NO 'HC1 (369.8): C, 64.96; H, 4.36; N, 3.79; Found: C, 65.20; H, 4.57; N, 3.79.

The filtrate was concentrated to 15 milliliters to give 60 milligrams (48% yield, based on starting material used) of nitidine chloride as light yellow crystals melting with decomposition at 275-277 C. (Literature: lshii et al., Yakagaku Zasshi, Vol. 92 (1972), at 118, melting point 275276 C.); )tmax (methanol): 234 (log 6 4.39), 270 (4.67), 290 (4.62), 299 (4.61 327 (4.60), and 380 nm (4.07).

The infrared spectrum of our synthetic compound was identical with that of the natural product provided by Drug Development Branch of the National Cancer Institute.

Anal. Calcd. for C H, ClNO '2H O (419.8): C, 60.07; H, 5.28; N, 3.34. Found: C, 60.15; H, 5.24; N, 3.34; m/e: 333 (M chloromethane-2 water, 52 (48%), 50 (chloromethane, 100%).

EXAMPLE 10 5,6-Dihydro-6-methoxynitidine (11 R and R are methyl; R and R taken together are methylene; R is methyl; R is methoxy).

due extracted with 100 milliliters of hot (50 C.) meth-.

anol (some insolublesolid was separated by filtration).

The volume of the solution was reduced to 20 milliliters and 0.45 gram (56% yield) of l l was collected as white crystals,- melting point 186-l 88 C. (dried at 78 C. in vacuo). Recrystallization from methanol yielded an analytically pure sample, melting point l89 19l C. (softened at 186 C.); Amax (chloroform) 2.38 (log 6 4.53), 283 (4.60) and 310 nm (4.40); Ash (chloroform) 325 nm (4.29 No moving spots were noted under the following thin-layer chromatography system: chloroform, silica gel. An Rf value of 0.2 was noted with chloroform, alumina. The product showed characteristics identical to those of the natural product. Prior to analysis, the sample was dried at 25 C. and 0.5 mm. for 16 hours.

Anal. Calcd. for C H NO (379.4): C, 69.64; H, 5.58; N, 3.69. Found: C, 70.00; H, 5.70; N, 3.73; m/e: 379 12.9%, M*), 348 (100%, M OCH 333 (17%, M OCH CH EXAMPLES 11-18 Synthesis of Allonitidine (l; R and R taken together are methylene; R and R are methyl; R is methyl; R is H; X is C1).

EXAMPLE 1 l 3,4'-Dimethoxy-3,4-methylenedioxychalcone (X).

To a warm (40 C.) solution of 41.5 grams (0.23 m0le)'of 3,4-dimethoxyacetophenone and 40.5 grams (0.27 mole) of piperonal in 220 milliliters of ethanol was added 60 milliliters of 10% aqueous sodium hydroxide. The mixture was warmed for 10 minutes at 4050 C; then stirred at room temperature for 2 hours. After standing overnight, the yellow crystalline product was collected by filtration, washed with water (3X 40 milliliters), and dried 'to give 72 grams (quantitative yield) of V melting point 127129 C. An analytical sample was prepared by recrystallization of 1.6 gram'of the product from 50 milliliters of ethanol, giving 1.4 gram of pure chalcone as yellow needles, melting .point l31-l33 C.; Amax (ethanol) 242 (log 6 4.23), 3.60 nm 4.53 I Anal. Calcd. for C H O (3l2.3): C, 69.22; H, 5.16. Found: C, 68.97; H, 5.26.

EXAMPLE 12 y-( ,4-Dimethoxyphenyl )-a-( 3 ,4-methylenedioxyphenyl )-y-oxobutyronitrile) (\LI A solution of 15 grams (0.23 mole) of potassium cyanide in 60 milliliters of water was added in 3 minutes, with stirring, to a hot (heated on a steam bath) solution of 36 grams (0.12 mole) of the product of Example 1 1 in 200 milliliters of 2-ethoxyethanol containing 7.5 milliliters (0.12 mole) of acetic acid. The resulting mixture washeated on a steam bath for 10 minutes and stirred at room temperature for 1 hour. To the mixture was added, at 0 C., 200 milliliters of water. The resulting white solid was collected by filtration, washed with water (3 X 150 milliliters), and dried to give 36 grams (92% yield) of melting point 159-161 C. Recrystallization from ethanol afforded an analytical sample, melting point 161l62 C Amax (ethanol) 230 (log e 4.34), 278 nm (4.16) Ash (ethanol) 306 nm (3.98).

Anal. Calcd. for C H NO (339.4): C, 67.25; H, 5.05; N, 4.13. Found: C, 67.02; H, 4.96; N, 4.03.

EXAMPLE 13 y 3,4 Dimethoxyphenyl )-oz-( 3 .4-methyle nedioxyphenyl )--y-oxo butyric Acid) (\Q l) A mixture of 20 grams (0.059 mole) of the product of Example 12 and 22 grams (0.55 mole) of sodium hydroxide in 250 milliliters of water and milliliters of ethanol was refluxed on a steam bath for 10 hours. It was cooled and acidified with 10% hydrochloric acid to pH 1. The resulting mixture was stirred for 2 hours then allowed to stand overnight. The solid was collected by filtration, washed with water and dried. to give 23 grams (quantitative yield) of V 1}. melting point l98-200 C. Recrystallization from ethanol yielded an analytically pure sample as white crystals, melting point 20l203 C.; Amax (ethanol) 229 (log 5 4.35 274 nm (4.27); Ash (ethanol) 294 nm (4.14).

Anal. Calcd. for C H O (358.4): C, 63.68; H. 5.06. Found: C, 63.79; H, 5.02.

EXAMPLE 14 6,7-Dimethoxy-2-(3,4-methylenedioxyphenyl)1-oxol,2,3,4-tetrahydronaphthalene) (1X) A mixture of 22 grams (0.062 mole) of the product of Example 13 and 3 grams of 10% Pd/C in 200 milliliters of acetic acid in the presence of 1.5 milliliters of 70% perchloric acid was hydrogenated at 5560 C. under 4 kg./cm for 2 hours. The catalyst was filtered from the warm reaction mixture and washed with acetic acid (3 X 40 milliliters). The combined filtrate and washings were evaporated to dryness in vacuo. The residue was extracted with benzene (4 X 300 milliliters). The benzene extract was washed with water (3 X 150 milliliters) and dried (sodium sulfate). Evaporation of solvent gave 20 grams yield) of the butyric acid; Amax (ethanol) 230,280 nm.

To a stirred suspension of 25.5 grams (0.12 mole) of phosphorus pe'ntachloride in milliliters of dry chloroform was added a solution of 40 grams (0.1 15 mole) of the butyric acid in 300 milliliters of chloroform at 0 C. The resulting mixture was stirred in an ice bath for 2 hours and then at room temperature for 16 hours. To this was added dropwise at 0 C. a solution of 15 milliliters (0.12 mole) of anhydrous stannic chloride in 40 milliliters of dry chloroform in 15 minutes. The mixture was stirred at 0 C.-for 3 hours and poured into a mixture of 450 milliliters of 10% hydrochloric acid and 200 grams of ice. The complex, which gradually decomposed, was extracted with chloroform (5 X 300 milliliters). The chloroform solution was washed successively with water (3 X 350 milliliters), 3% sodium hydroxide (3 X 350 milliliters) and water (3 X 350 milliliters). The washings were back-extracted with chloroform. The combined chloroform solution was dried (sodium sulfate) and treated with Celite. The solvent was removed in vacuo and the residue triturated with 40 milliliters of methanol. The resulting solid was collected by filtration, washed with cold methanol, and dried to give 29.4 grams (77% yield) of TX, melting point 168-170 C. Recrystallization from ethanol yielded an analytical sample as white needles, melting point 173?175 C; Amax (ethanol) 233 (log 64.31), 277 (4.13), 313 nm (3.91), m/e: 326 (M Anal. Calcd. for C H O (326.4): C, 69.93; H, 5.56. Found: C, 70.16; H, 5.50.

EXAMPLE l 6.7-Dimethoxyl formamido2-( 3.4- methylenedioxyphenyl )-l ,2,3 ,4-tetrahydronaphthalene (25). i

A stirred mixture of 24 grams (0.074 mole of the product of Example 14, 3.5 grams of ammonium sulfate, 60 milliliters of formamide and 3.5 milliliters of formic acid was heated in an oil bath at 185 C. for 6 hours. Addition ofa 3.5 milliliter portion of formic acid to the reaction mixture was made three times at hourly intervals. The reaction mixture was cooled and to it was added 150 milliliters of water followed by 250 milliliters of chloroform. The mixture was stirred for minutes and transferred into a separatory funnel. The chloroform layer was separated and the aqueous layer extracted three times with chloroform. The combined chloroform solution was washed with water and dried (sodium sulfate). The solvent was evaporated in vacuo and the residue triturated with 50 milliliters of methanol. After it had stood overnight, the resulting white solid was collected by filtration to give 20.8 grams of crude X, melting point 150-190 C. The crude product was purified on a neutral alumina column using chloroform as the eluent. Evaporation of the chloroform solution followed by recrystallization of the residue from methanol gave a pure product, melting point 201-203 C.; )tmax (ethanol) 233 (log e 4.19), 285 nm (3.98), m/e: 355 (M Anal. Calcd. for C H NO (355.4): C, 67.59; H, 5.96; N, 3.94. Found: C, 67.44; H, 5.68; N, 3.99.

EXAMPLE l6 2,3-Dimethoxy-8 ,9-methylenedioxy-4b, l0b,1 1,12- tetrahydrobenzo[c]phenanthridine (X I).

To a stirred suspension of 3 grams (0.0085 mole) of the product of Example 15 in 30 milliliters of toluene was added 7.5 milliliters of redistilled phosphorus oxychloride. The mixture was heated at 100-110 C. for 30 minutes, during which time a brown solution formed followed by precipitation of a yellow solid. The reaction mixture was cooled to 45 C., the solid was collected by filtration, washed with hot toluene and ether, and dried to give 2.4 grams of the hydrochloride salt of X I, melting with decomposition at 234-235 C. The salt was suspended in 30 milliliters of methanol, basified with methanolic ammonia, and chilled. The resulting white solid was collected by filtration, washed with methanol, and dried to give 1.2 grams (42% yield) of X I, melting point 208210 C. Recrystallization from methanol and pyridine yielded white crystals, melting point 2l0212 C.; Amax (ethanol) 232 (log e 4.61), 280 (4.02), 316 nm (3.72), m/e: 337 (M Anal. Calcd. for C H NO (337.4): C, 71.20; H, 5.68; N, 4.15. Found: C, 71.16; H, 5.88; N, 4.15.

EXAMPLE 17 2,3-Dimethoxy-8,9-methylenedioxybenzo[ c]phenanthridine (X11).

A mixture of 0.5 gram (0.0015 mole) of the product of Example 16, 0.2 gram of 30% palladium-on-charcoal and 7 milliliters of Dow Corning 550 fluid was heated under nitrogen at 255-260 C. for 2 hours with stirring. The mixture was cooled, diluted with 30 milliliters of chloroform, and filtered. The catalyst was extracted continuously with chloroform. The combined filtrate and extract was evaporated in vacuo to a syrup which, upon trituration with 10 milliliters of ethanol. yielded a light yellow solid, This.was collected by filtration. washed with ethanol and petroleum ether (boiling point 35-60 C.) and dried to give 04 gram yield) of X l l. melting point 275-277 C. (recrystallized from pyridinemethanol); Amax (chloroform) 273 (log 6 4.83), 283 (4.08). 305 (4.38). 333 (3.98). 351 (3.76), 368 nm (3.48); m/e: 333 (M* Anal. Calcd. for C H NO (333.4): C. 72.06; H. 4.54; N, 4.20. Found: C. 72.22; H, 4.79: N. 4.42.

EXAMPLE l8 Allonitidine Methyl Sulfate (2,3-Dimethoxy-8.9- methylenedioxy-5-methylbenzolclphenanthridinium Methyl Sulfate, or 2,3-Dim ethoxy-5- methylbenzo[c][ l ,3 ]dioxolo[4.5-jlphenanthridinium Methyl Sulfate) 1).

To a hot solution of 11 grams (0.33 mole) of the product of Example 17 in 1 l0 milliliters of xylene and 250 milliliters of nitrobenzene was added 30 milliliters of dimethyl sulfate. The mixture was heated at l75-180 C. for 20 minutes with stirring whereupon a yellow solid gradually separated from the reaction mixture. The mixture was cooled and diluted with 250 milliliters of ether. The yellow solid was collected by filtration on a fritted glass funnel, washed with ether and pe troleum ether (boiling point 3560 C.) and dried to give 13.9 grams (91% yield) of product, melting with decomposition at 322324 C. An analytical sample prepared by recrystallization from methanol, melted with decomposition at 328-330 C. Mnax (methanol), 231 (10g e 4.43), 272 (4.80), 302 (4.59), 328 (4.51) and 390 (3.98); m/e: 333 (MT (CH SO Anal. Calcd. for C H NO S (459.5): C, 57.51; H. 4.61; N, 3.05. Found: C, 57.71; H, 4.41; N, 2.94.

EXAMPLE l9 5,6-Dihydro-6-methoxyallonitidine (5,6-Dihydro-5- methyl-8,9-methylenedioxy-2,3,6-trimethoxybenzo[c]- phenanthridine or 5,6Dihydro-5-methyl-2,3,6- trimethoxybenzo[c][1,3]dioxo1o[4,5-j]- phenanthridine) 11 R and R taken together are methylene; R R and R are methyl; R is methoxy).

A mixture of 1.4 grams (3 millimoles) of finely ground allonitidine methyl sulfate and 200 milliliters of 28% aqueous ammonia was stirred in an ice bath for 30 minutes. The mixture was extracted with chloroform (5 X 200 milliliters), the extract washed with water (50 milliliters) and dried (sodium sulfate). To the dried solution was added 50 milliliters of methanol. The resulting mixture was evaporated below 30C. in vacuo. The pasty residue was extracted with milliliters of hot methanol. The methanol extract was concentrated to 50 milliliters and cooled. White crystals, which gradually separated from the solution, were collected by filtration, washed with ether and petroleum ether (boiling point 35-60C.), and dried to give 0.6 gram (52% yield) of melting with decomposition at 21 l2l3C.; Amax (chloroform) 281 (log 4.63), 311 nm (4.38); m/e: 379 (M*), 348 (M OCH 333 (M OCH CH Anal. Calcd. for C H NO (379.4): C, 69.64; H, 5.58; N, 3.69. Found: C, 69.40; H, 5.49; N, 3.62.

EXAMPLE 20 2,3 ,8,9-Tetramethoxy-5-methylbenzo[c lphenanthridinium Methyl Sulfate (1; R,, R R R and R are methyl; R is H; X is CH SO Material prepared by the method of Examples 11-18 gave a tetramethoxy compound melting at 31 l-3l2C. The reported melting point is 305308 C.; Bailey et al.-, J. Chem. Soc. (1950), at 2277.

EXAMPLE 2l 5,6-Dihydro-5-methyl-2,3,6,8,9-pentamethoxybenzo[c]phenanthridine ll; R R R R and R are methyl; R is methoxy).

The product of Example 20 was converted, in 63% yield, toll according to the method of Example 19. The product melted at 2l22l4 C.; )tmax (chloroform) 281 (log e 4.62) 310 nm (4.36); m/e: 395 (M), 364 (M OCH 349 (M OCH CH Anal. Calcd. for C H NO (395.5): C, 69.86; H, 6.37; N, 3.54. Found: C, 70.08; H, 6.14; N, 3.58.

What is claimed is:

l. A method for the synthesis of oxygenated benzo[c]phenanthridine compounds of the formula wherein R R R and R are selected independently from the group consisting of C -C alkyl, H, benzyl; R and R taken together are methylene and R and R taken together are methylene; R is selected from the group consisting of C C alkyl groups; R; is selected from the group consisting of H- and C -C alkoxy groups; and X is an anion selected from the group consisting of chloride, bromide, iodide, hydroxide, methosulfate, and the monovalent equivalent of polyvalent anions such as sulfate and phosphate comprising the steps of:

condensing 3,4 alkoxy benzaldehyde with 3,4.alkoxy acetophenone under alkaline conditions to form a chalcone; condensing the chalcone with a cyanide under acidic conditions to form a ketobutyronitrile; hydrolyzing the ketobutyronitrile in a one-step basecatalyzed reaction to a ketobutyric acid; reducing the ketobutyric acid to a butyric acid; cyclizing the butyric acid to a tetralone using phosphorus pentachloride and stannic chloride as cyclizing agents; converting the tetralone to a formamide in a modified Leuckart reaction wherein the reaction mixture is heated at about 180-185,"C.;

cyclizing the formamide to a tetrahydrobenzo[c]- phenanthridine with phosphorus oxychloride: aromatizing the tetruhydrobenzo[clphenanthridine over a palladium-on-charcoal catalyst in an inert fluid of the phenyl polysiloxane type to a benzo[c]- phenanthridine; Y

and quaternizing the benzo[c]phenanthridine with X to produce the product.

2. The methodofclaim 1, wherein R R R and R are selected independently from C C alkyl groups, H, and benzyl; R is methyl; R is selected from the group consisting of H- and C -C alkoxy; and X is selected from the group consisting of chloride, hydroxide and methosulfate.

3. The method of claim l,wherein R and R taken together are methylene; R and R are methyl; R is methyl; R is selected from the group consisting of H- and methoxy, and X is selected from the group consisting of chloride, hydroxide and methosulfate.

4. The method of claim 1, wherein R and R are methyl, R and R taken together are methylene; R is methyl; R is selected from the group consisting of H- o e x wherein R and R are selected independently from the group consisting of C -C alkyl, R is selected from the group consisting of C -C alkyl, R is selected from the group consisting of H and C -C alkoxy, and X is an anion selected from the group consisting of chloride, bromide, iodide, hydroxide, methosulfate, and the monovalent equivalent of polyvalent anions such as sulfate and phosphate.

8. Allonitidine compounds of claim 7, wherein R R and R are methyl; R is selected from the group consisting of H and methoxy; and X is selected from the group consisting of chloride, hydroxide and methosulfate. 

1. A method for the synthesis of oxygenated benzo(C)phenanthridine compounds of the formula
 2. The method of claim 1, wherein R1, R2, R3 and R4 are selected independently from C1-C4 alkyl groups, H, and benzyl; R5 is methyl; R6 is selected from the group consisting of H-and C1-C4 alkoxy; and X is selected from the group consisting of chloride, hydroxide and methosulfate.
 3. The method of claim 1, wherein R1 and R2 taken together are methylene; R3 and R4 are methyl; R5 is methyl; R6 is selected from the group consisting of H- and methoxy, and X is selected from the group consisting of chloride, hydroxide and methosulfate.
 4. The method of claim 1, wherein R1 and R2 are methyl, R3 and R4 taken together are methylene; R5 is methyl; R6 is selected from the group consisting of H- and methoxy, and X is selected from the group consisting of chloride, hydroxide and methosulfate.
 5. The method of claim 1, wherein the quaternized benzo(c)phenanthridine is a chloride obtained by treating a methosulfate with an ionic chloride.
 6. The method of claim 1, wherein the quaternized benzo(c)phenanthridine compound is a methosulfate, which is treated with an aqueous ammoniacal solution to yield a 5,6-dihydrobenzo(c)phenanthridine compound.
 7. ALLONITIDINE COMPOUNDS OF THE FORMULA
 8. Allonitidine compounds of claim 7, wherein R3, R4 and R5 are methyl; R6 is selected from the group consisting of H- and methoxy; and X is selected from the group consisting of chloride, hydroxide and methosulfate. 